Rationale and Design of the Comparative Effectiveness of ICD Versus Non-ICD Therapy in Contemporary Heart Failure Patients at a Low Risk for Arrhythmic Death (CONTEMP-ICD) trial.

Background: Current recommendations for a prophylactic (primary prevention) implantable cardioverter defibrillator (ICD) in patients with both ischemic and non-ischemic heart failure with reduced ejection fraction (HFrEF) originate from clinical trials conducted in selected patients over 20 years ago that showed an overall statistically significant survival benefit associated with a primary prevention ICD in the range of 23%-34%. The recent introduction of angiotensin receptor-neprilysin inhibitors [ARNI] and sodium glucose co-transporter 2 inhibitors [SGLT2i]) was shown to further reduce the risk of sudden cardiac death (SCD) in patients with HFrEF. Thus, there is an unmet need appropriately designed comparative effectiveness clinical trials aimed to reassess the survival benefit of a primary prevention ICD in contemporary patients with HFrEF.

Clinical care of family members of patients with dilated cardiomyopathy.

Genetic family screening following the detection of a pathogenic or likely pathogenic variant in a proband with dilated cardiomyopathy (DCM) remains one of the main applications of genetic testing. While cardiac screening is recommended for all first-degree relatives, the a priori risk among family members varies. Consequently, screening regimens should be tailored according to both genetic and clinical information at the individual and familial level.

The Clinical Significance of Atrial Fibrillation in Non-High-Risk Brugada Syndrome: The BruFib Study.

Background: Atrial fibrillation (AF) occurs in up to 20% of patients with Brugada syndrome (BrS), yet its risk factors and prognostic implications remain uncertain.

Objectives: This study sought to identify risk factors for AF in patients with non-high-risk BrS and to evaluate the impact of AF on ventricular arrhythmias (VAs), sick sinus syndrome (SSS), and stroke in non-high-risk BrS.

Methods: This was a multicenter, retrospective study conducted across 20 international centers.

Novel start codon variant in the 5'UTR of LDLR associated with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a genetic disorder due to pathogenic variants in LDLR, APOB, and PCSK9 genes, characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentration and a significantly increased risk of premature coronary heart disease. Annotating whole genome sequencing data of 536 FH patients using the VEP plugin UTRannotator, we identified a novel variant c.-35C > G in the 5' untranslated region (5'UTR) of LDLR, predicted to introduce an upstream translation initiation codon and upstream open reading frame (uORF) that is out of frame with the LDLR coding sequence.

Synthetic electrocardiograms for Brugada syndrome: from data generation to expert cardiologists evaluation.

Aims: Synthetic electrocardiograms (ECGs) for inherited cardiac diseases may overcome the issue related to data scarcity for artificial intelligence (AI)-based algorithms. This study aimed to evaluate experienced cardiologists' ability to differentiate synthetic and real Brugada ECGs.

Methods And Results: A total of 2244 ECG instances (50% synthetic generated by a generative adversarial network, 50% real Brugada patients' ECGs) were evaluated by 7 cardiologists, each with >15 years of experience.

High incidence of malignant arrhythmias and heart failure in patients with RBM20-associated cardiomyopathy: A multicenter cohort study and review of the literature.

Background: Patients with RBM20 cardiomyopathy present with an aggressive phenotype, associated with premature malignant arrhythmias, sudden cardiac death, and progressive heart failure (HF). This study aimed to investigate genotype-phenotype correlations, clinical outcomes, and causes of death in patients with RBM20-associated cardiomyopathy and review the current literature.

Methods: The cohort included patients with cardiomyopathy harboring pathogenic (P) or likely pathogenic (LP) RBM20 variants.

The diagnostic role of pharmacological provocation testing in cardiac electrophysiology: a clinical consensus statement of the European Heart Rhythm Association and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC, the ESC Working Group on Cardiovascular Pharmacotherapy, the Association of European Paediatric and Congenital Cardiology (AEPC), the Paediatric & Congenital Electrophysiology Society (PACES), the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS).

The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it.

Rare disease gene association discovery in the 100,000 Genomes Project.

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published.

Reassessing the need for primary prevention implantable cardioverter-defibrillators in contemporary patients with heart failure.

The main function of the implantable cardioverter-defibrillator (ICD) is to protect against sudden cardiac death (SCD) due to ventricular tachyarrhythmia (VTA). Current guidelines provide a recommendation to implant a prophylactic ICD for the primary prevention of SCD in individuals having heart failure with reduced ejection fraction (HFrEF) who never experienced a previous sustained VTA. However, these recommendations are based on clinical trials conducted more than 20 years ago and may not be applicable to contemporary patients with HFrEF who have a lower arrhythmic risk as a result of advances in heart failure medical therapies.

Reassessing the need for primary prevention implantable cardioverter-defibrillators in contemporary patients with heart failure.

The main function of the implantable cardioverter-defibrillator (ICD) is to protect against sudden cardiac death (SCD) due to ventricular tachyarrhythmia (VTA). Current guidelines provide a recommendation to implant a prophylactic ICD for the primary prevention of SCD in individuals having heart failure with reduced ejection fraction (HFrEF) who never experienced a previous sustained VTA. However, these recommendations are based on clinical trials conducted more than 20 years ago and may not be applicable to contemporary patients with HFrEF who have a lower arrhythmic risk as a result of advances in heart failure medical therapies.

Influence of age and sex on the diagnostic yield of inherited cardiac conditions in sudden arrhythmic death syndrome decedents.

Aims: Sudden arrhythmic death syndrome (SADS) refers to a sudden death, which remains unexplained despite comprehensive post-mortem examination and a toxicological screen. We aimed to investigate the impact of age and sex on the overall diagnostic yield and underlying aetiology in decedents with SADS using a combined approach of familial evaluation (FE) and molecular autopsy (MA).

Methods And Results: Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included.

The Impact of Coronary Ischemia Assessment on Outcomes in Those With Scar-Dependent Ventricular Tachycardia.

Background: Guidance and outcomes of coronary ischemia assessment (IA) in those with structural heart disease (SHD), presenting with monomorphic ventricular tachycardia (MMVT) is unclear.

Objectives: To assess the impact of IA on arrhythmic and non-arrhythmic outcomes in those with SHD.

Methods: Patients presenting with MMVT over a 6-year period to a tertiary center were retrospectively analyzed.

Ethnicity and sudden cardiac death in athletes: insights from a large United Kingdom registry.

Aims: The relationship between ethnicity and causes of sudden cardiac death (SCD) in athletes is poorly understood.

Objectives: To investigate aetiology of SCD among different ethnicities in a large cohort of athletes.

Methods And Results: Between 1994 and November 2022, 7880 cases of SCD were consecutively referred from all over the United Kingdom to our national cardiac pathology centre; 848 (11%) were athletes.

The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study.

Aims: Brugada syndrome (BrS) diagnosis and risk stratification rely on the presence of a spontaneous type 1 (spT1) electrocardiogram (ECG) pattern; however, its spontaneous fluctuations may lead to misdiagnosis and risk underestimation. This study aims to assess the role for repeat high precordial lead (HPL) resting and ambulatory ECG monitoring in identifying a spT1, and evaluate its prognostic role.

Methods And Results: HPL resting and ambulatory monitoring ECGs of BrS subjects were reviewed retrospectively, and the presence of a spT1 associated with ventricular dysrhythmias and sudden cardiac death (SCD).